Cellular interactions which occur during an immune response are regulated by members of several families of cell surface receptors, including the tumor necrosis factor receptor (TNFR) family. The TNFR family consists of a number of integral membrane glycoprotein receptors many of which, in conjunction with their respective ligands, regulate interactions between different hematopoietic cell lineages (Smith et al., The TNF Receptor Superfamily of Cellular and Viral Proteins: Activation, Costimulation and Death, 76:959-62, 1994; Cosman, Stem Cells 12:440-55, 1994).
One such receptor is BCMA, a nonglycosylated integral membrane type I protein that is preferentially expressed in mature B lymphocytes (Gras et al., Int. Immunol. 17:1093-106, 1995). BCMA is located on the cell surface, as well as in a perinulear Golgi-like structure. Overexpression of BCMA in 293 cells activates NF-kappa B, Elk-1, the c-Jun N-terminal kinase, and the p38 mitogen-activated protein kinase, thus producing signals for cell survival and proliferation (Hatzoglou et al., J. Immunol., 165: 1322-30, 2000). Another such receptor is TACI, transmembrane activator and CAML-interactor (von Bülow and Bram, Science 228:138-41, 1997 and WIPO Publication WO 98/39361). TACI is a membrane bound receptor having an extracellular domain containing two cysteine-rich pseudo-repeats, a transmembrane domain and a cytoplasmic domain that interacts with CAML (calcium-modulator and cyclophilin ligand), an integral membrane protein located at intracellular vesicles which is a co-inducer of NF-AT activation when overexpressed in Jurkat cells. A third receptor from the TNFR family expressed on the surface of B cells is BAFF-R (Thompson et al., Science, 293: 2108-11, 2001. Signaling of this receptor, also known as BAFF/BLyS receptor 3 (BR3), promotes processing of the transcription factor NF-kappaB2/p100 to p52. This cascade is physiologically relevant for survival of B cells, and therefore, the progression of B cells to maturation (Claudio et al., Nat. Immunol., 3: 898-9, 2002; Kayagaki et al., Immunity, 17: 515-24, 2002).
A number of BLyS and/or APRIL antagonists have been developed in order to block the binding of these ligands to the receptor members of the family, in order to block results of this binding which include but should not be limited to B cell costimulation, plasmablast and plasma cell survival, Ig class switching, enhanced B-cell antigen presenting cell function, survival of malignant B cells, development of B-1 cell function, B cell development beyond the T-1 stage, and complete germinal centre formation. Some of these molecules can also bind to and block the effect of APRIL on B cells and other components of the immune system (Dillon et al. (2006) Nat. Rev. Drug Dis. 5, 235-246). Molecules that have been developed to affect B cell function by interfering with BLyS and/or APRIL binding include BLyS antibodies such as Lymphostat-B (Belimumab) (Baker et al, (2003) Arthritis Rheum, 48, 3253-3265 and WO 02/02641); receptor-extracellular domain/Fc domain fusions proteins such as TACI-Ig, including one particular embodiment, atacicept (U.S. Patent Application No. 20060034852), BAFF-R-Fc (WO 05/0000351), and BCMA-Ig or other fusion proteins utilizing receptor extracellular domains. A further class of BLyS and/or APRIL antagonists include other molecules relying on BLyS binding ability to block binding to its receptors such as AMG 623, receptor antibodies, and other molecules disclosed in WO 03/035846 and WO 02/16312.
There remains a need in the art for further identification of cell surface expression patterns of these TNFR family members that are statistically associated with autoimmune disease, such as systemic lupus erythromatosus (SLE). Such information is important for identifying individuals who have a propensity toward developing such autoimmune diseases, are in an active disease state, and for identifying those that will respond favorably to BLyS and/or APRIL antagonist treatment of these diseases. The present invention addresses this need by providing a cell surface expression pattern associated with autoimmune diseases and providing diagnostic tests determining the presence of this expression pattern, namely increased BCMA expression on B cells for those suffering from autoimmune disease as compared to healthy controls.